Immunosenescence starts from thymic involution, while age-related thymic involution results from thymic microenvironment changes regulated by multiple genes. Our hypothesis is the aged atrophic thymus must show changes in molecular features and cellular profiles that are not currently known, and transcription factors regulating thymic microenvironment built up mostly by thymic epithelial cells might be involved in the aging-related thymic involution process. Our approach is to investigate the aged atrophic thymus molecular features and cellular profiles focusing on K5/K8 co-localization on thymic epithelial cells, TN.1 hematopoietic progenitor cell subsets based on cKit and HAS expression, as well as the expression of two classes of Foxnl transcription; meanwhile test whether down regulation of the Foxn1 signal in medulla, cortex and total TECs in adult thymus can sufficiently induce aging-related thymic involution with site- and time- tissue-specific Cre-recombinase mouse model. These studies may ultimately lead to understanding the molecular mechanisms of age-related thymic involution and make possible strategies to reverse the function of the aged thymus.